A convenient synthesis of 4-(2-hydroxyethyl)indolin-2-one, a useful intermediate for the preparation of both dopamine receptor agonists and protein kinase inhibitors

Article abstract of DOI:10.1007/s00706-014-1211-z

This paper describes a practical approach to the preparation of 4-(2-hydroxyethyl)indolin-2-one, a key intermediate in the synthesis of dopaminergic agonists such as ropinirole - a drug used in the treatment of Parkinson's disease and restless legs syndrome - and of two sets of protein kinase inhibitors. The sequence starts from commercially available 2-(2-methyl-3-nitrophenyl)acetic acid, which is converted in five steps into the desired target compound. This procedure offers a convenient alternative route to existing methodologies, given its milder reaction conditions, ease of implementation, and its overall yield (59 %).

Full text of DOI:10.1007/s00706-014-1211-z

Monatsh Chem
DOI 10.1007/s00706-014-1211-z
ORIGINAL PAPER
A convenient synthesis of 4-(2-hydroxyethyl)indolin-2-one,
a useful intermediate for the preparation of both dopamine
receptor agonists and protein kinase inhibitors
•
Carlo Matera Marta Quadri Silvia Pelucchi
•
•
•
Marco De Amici Clelia Dallanoce
Received: 23 January 2014 / Accepted: 23 March 2014
Ó Springer-Verlag Wien 2014
Abstract This paper describes a practical approach to the
preparation of 4-(2-hydroxyethyl)indolin-2-one, a key
intermediate in the synthesis of dopaminergic agonists such
as ropinirole—a drug used in the treatment of Parkinson’s
disease and restless legs syndrome—and of two sets of
protein kinase inhibitors. The sequence starts from com-
mercially available 2-(2-methyl-3-nitrophenyl)acetic acid,
which is converted in five steps into the desired target
compound. This procedure offers a convenient alternative
route to existing methodologies, given its milder reaction
conditions, ease of implementation, and its overall yield
(59 %).
for cocaine [4, 5]. A few of the known synthetic routes to
this drug substance involve 4-(2-hydroxyethyl)indolin-2-
one (2) as a key intermediate (Fig. 1) [6–8]. Moreover, in
the framework of a research project aimed at the pharma-
cological investigation of novel dopaminergic compounds,
we designed a new series of ligands (4) incorporating the
molecular skeleton of ropinirole (C. Matera et al., unpub-
lished results). For such a purpose, we needed 4-[2-
(propylamino)ethyl]indolin-2-one (3) as a synthetic inter-
mediate, which in turn can be easily derived from the
primary alcohol 2 (Fig. 1). Compound 2 also represents an
important building block in the synthesis of two sets of
protein kinase inhibitors such as 5a and 5b (Fig. 1),
potentially useful as anticancer agents [9–14].
Keywords D2/D3 agonists Á Heterocycles Á
Indolin-2-ones Á One-pot synthesis Á Ropinirole Á
Synthetic improvement
Since we needed to prepare intermediate 2, which is of
established importance to medicinal chemistry, we first
attempted to follow the synthetic procedures already
reported in the literature. However, due to disadvantages
such as long steps, low yields, and inconvenient operations,
we then developed a more convenient synthetic sequence.
Introduction
Ropinirole (RequipÒ, RoparkÒ, AdartrelÒ, 1), a D2/D3/5-
HT1A receptor agonist (Fig. 1), is currently being used or
tested for the treatment of a variety of disorders, including
Parkinson’s disease [1], bipolar depression [2], and restless
legs syndrome [3]. Recently, ropinirole has also been tested
as a treatment for cocaine abuse, and is reported to be
effective at reducing the subjective ‘‘rush’’ of and craving
Results and discussion
Initially, we evaluated a known preparation of 2 [6, 7, 15],
as depicted in Scheme 1. This six-step route makes use of
cheap reagents and has been applied on a relatively large
scale to the synthesis of ropinirole, though it is character-
ized by an overall yield of just 29 %. In particular, in our
hands, the cyclization step (9–10) was very low-yielding
(about 8 %), thus discouraging the application of the whole
synthetic sequence. It is worth noting that a high-yield
procedure for the synthesis of 2, based on slight modifi-
cations of the protocol illustrated in Scheme 1, was
recently claimed in the patent literature [8]. Nevertheless,
M. Quadri and S. Pelucchi contributed equally to this work.
C. Matera (&) Á M. Quadri Á S. Pelucchi Á M. De Amici Á
C. Dallanoce
Dipartimento di Scienze Farmaceutiche (Sezione di Chimica
`
Farmaceutica ‘‘P. Pratesi’’), Universita degli Studi di Milano,
Via Luigi Mangiagalli, 25, 20133 Milan, Italy
e-mail: carlo.matera@unimi.it
123

C. Matera et al.
Fig. 1 Structure of target
compound 2 and its application
in medicinal chemistry
according to our evaluation, the overall yield of this variant
was only 10 %.
Compound 2 was finally converted into the corre-
sponding secondary amine 3 via nucleophilic substitution
of the bromide 21a or the tosylate 21b (Scheme 3). Anal-
ogously to what is seen in similar cases [20], nucleophilic
substitution leading to 3 was more efficient when tosylate
was used rather than bromide. In fact, the reaction between
bromide 21a and n-propylamine produced similar amounts
of substitution (3, 45 % yield) and elimination (22, 35 %
yield) products. Conversely, the use of tosylate 21b
selectively promoted the substitution reaction and mark-
edly improved the secondary amine 3 (87 % yield) to
styrene 22 (5 % yield) ratio.
Thus, we aimed at synthesizing the target secondary
amine 3 while bypassing the primary alcohol 2. We took as
a model the original synthesis of ropinirole (1, Scheme 2)
[16, 17] from commercially available 2-methyl-3-nitro-
phenylacetic acid (12), by replacing di-n-propylamine with
benzyl-n-propylamine. However, this synthetic route
resulted in many by-products and required complicated
purification steps, affording the desired secondary amine 3
only in trace amounts (Scheme 2).
Therefore, we decided to modify the latter synthetic
procedure as reported in Scheme 3, and prepared to this
end 2-(2-methyl-3-nitrophenyl)ethanol (17) in 96 % yield
by reduction of 12 with borane tetrahydrofuran complex
[18]. Subsequent protection of the hydroxyl group by
conversion to the corresponding benzyl ether 18, followed
by homologation with diethyl oxalate and sodium hydride
in DMF, provided the intermediate pyruvic acid ethyl ester
19 in a considerably higher overall yield (69 %) than the
yield of 15b obtained via the previous synthetic route [19].
Treatment of 19 with hydroperoxide anion afforded the
protected phenylacetic acid 20 (99 % yield), which, upon
palladium-catalyzed hydrogenation in ethanol, underwent
an efficient one-pot cyclization/deprotection, giving rise to
the desired indolin-2-one 2 in 90 % yield.
In conclusion, we developed an improved synthetic
route to 4-(2-hydroxyethyl)indolin-2-one (2), characterized
by a lower number of steps and a considerably higher
overall yield (59 % vs. 29 %) than the most convenient
known protocol. Moreover, our synthesis makes use of
readily available and cheap reagents, simple work-up
procedures, and requires only one chromatographic purifi-
cation in five steps. This synthetic route allowed us an easy
access to a set of novel dopaminergic compounds (results
for these will be published in due course), and it could be
used as an alternative to the known procedures for the
synthesis of the drug ropinirole (1) or for the synthesis of
potential anticancer agents that act as protein kinase
inhibitors (5a and 5b).
123

A convenient synthesis of 4-(2-hydroxyethyl)indolin-2-one
Scheme 1
Experimental
(St. Louis, MO, USA) and used directly as obtained com-
mercially, unless otherwise noted.
1H NMR and 13C NMR spectra were recorded with a
Varian (Palo Alto, CA, USA) Mercury 300 (1H:
300.063 MHz, 13C: 75.451 MHz) spectrometer at 20 °C.
Chemical shifts (d) are expressed in ppm and coupling
constants (J) in Hz. TLC analyses were performed on
commercial silica gel 60 F254 aluminum sheets; spots were
further evidenced by spraying with a dilute alkaline
potassium permanganate solution or a phosphomolybdic
acid solution (20 wt% in ethanol). Preparative separations
were performed using flash column chromatography on
silica gel (60–200 mesh). Melting points were determined
on a model B540 Bu¨chi (Flawil, Switzerland) apparatus.
Electrospray ionization (ESI) mass spectra were obtained
on a Varian 320 LC–MS/MS instrument. Data are reported
as the mass-to-charge ratios (m/z) of the corresponding
positively charged molecular ions. Microanalyses (C, H, N)
of new compounds agreed with the theoretical value within
0.4 %. All reagents were purchased from Sigma–Aldrich
2-(2-Methyl-3-nitrophenyl)ethanol (17)
2-Methyl-3-nitrophenylacetic acid (12, 2.00 g, 10.25
mmol) was placed in a flame-dried round-bottomed flask
under an argon atmosphere and dissolved in 20 cm3 THF.
To this solution, 20.5 cm3 1 M BH3-THF (2 equiv) were
added dropwise via syringe at 0 °C and stirred at room
temperature for 3 h. The reaction mixture was quenched
with a saturated solution of NaHCO3, diluted with water,
and extracted with ethyl acetate. The combined organic
layers were then washed with brine, dried over anhydrous
Na2SO4, filtered, and the solvent was removed in vacuo to
afford 1.78 g (96 %) 17 as a pale yellow oil. Rf = 0.4
(cyclohexane/ethyl acetate 1:1); 1H NMR (300 MHz,
CDCl3): d = 2.37 (s, 3H), 2.63 (bs, 1H), 2.92 (t, 2H,
J = 6.9 Hz), 3.78 (t, 2H, J = 6.9 Hz), 7.21 (dd, 1H,
J = 7.6, 8.0 Hz), 7.37 (d, 1H, J = 7.6 Hz), 7.55 (d, 1H,
J = 8.0 Hz) ppm; 13C NMR (75 MHz, CDCl3): d = 15.0,
36.7, 62.3, 122.4, 126.5, 130.7, 134.1, 140.1, 151.6 ppm;
123

C. Matera et al.
Scheme 2
MS: m/z calcd. for C9H13NO4 [M?H2O] 199.08, found
128.7, 130.75, 134.0, 138.5, 140.6, 151.7 ppm; MS:
199.1.
m/z calcd. for C16H19NO4 [M?H2O] 289.13, found 289.1.
1-[(2-Methyl-3-nitrophenethyloxy)methyl]benzene
Ethyl 3-[2-[2-(benzyloxy)ethyl]-6-nitrophenyl]-2-
(18, C16H17NO3)
oxopropanoate (19, C20H21NO6)
60 % Sodium hydride (w/w) in mineral oil (0.41 g,
10.31 mmol) was added portionwise to a well-stirred
solution of 1.78 g 17 (9.82 mmol) in 15 cm3 dry THF at
0 °C under argon. After 30 min, a solution of 1.76 g benzyl
bromide (10.31 mmol) in 12 cm3 dry THF was added
dropwise and the reaction mixture was stirred at room
temperature for 8 h. The reaction was then quenched with
cold water, poured into a saturated solution of NH4Cl, and
extracted with ethyl acetate. The combined organic layers
were then washed with brine, dried over anhydrous
Na2SO4, filtered, and the solvent was removed in vacuo
to yield 2.53 g 18 (95 %) as a yellow oil. Rf = 0.4
(cyclohexane/ethyl acetate 9:1); 1H NMR (300 MHz,
CDCl3): d = 2.43 (s, 3H), 3.04 (t, 2H, J = 6.9 Hz), 3.72
(t, 2H, J = 6.9 Hz), 4.56 (s, 2H), 7.24 (dd, 1H, J = 7.6,
8.0 Hz), 7.35 (m, 5H), 7.43 (d, 1H, J = 7.6 Hz), 7.62 (d,
1H, J = 8.0 Hz) ppm; 13C NMR (75 MHz, CDCl3):
d = 15.1, 34.2, 69.8, 73.3, 122.4, 126.5, 127.8, 128.0,
60 % Sodium hydride (w/w) in mineral oil (1.28 g,
32.05 mmol) was added portionwise to a well-stirred
solution of 1.74 g 18 (6.41 mmol) in 15 cm3 dry DMF at
0 °C under argon. After stirring for 20 min at room
temperature (reddish color), a solution of 7.50 g diethyl
oxalate (51.31 mmol) in 15 cm3 dry DMF was added
dropwise and the reaction mixture was stirred at room
temperature for a further 8 h. The reaction was then
quenched with a saturated solution of NH4Cl, diluted with
water, and extracted with ethyl acetate. The collected
organic layers were washed with brine, dried over anhy-
drous Na2SO4, filtered, and concentrated in vacuo, and the
crude product was purified by column chromatography on
silica gel (cyclohexane/ethyl acetate 4:1) to afford 1.71 g
(72 %) 19 as a yellow oil. Rf = 0.5 (cyclohexane/ethyl
acetate 8:2); 1H NMR (300 MHz, CDCl3): d = 1.39 (t, 3H,
J = 7.2 Hz), 2.97 (t, 2H, J = 6.6 Hz), 3.65 (t, 2H,
J = 6.6 Hz), 4.37 (q, 2H, J = 7.2 Hz), 4.45 (s, 2H), 4.57
123

A convenient synthesis of 4-(2-hydroxyethyl)indolin-2-one
Scheme 3
(s, 2H), 7.31 (m, 6H), 7.52 (d, 1H, J = 7.7 Hz), 7.90 (d,
1H, J = 8.2 Hz) ppm; 13C NMR (75 MHz, CDCl3):
d = 14.3, 30.0, 34.1, 39.5, 63.1, 70.3, 73.3, 123.7, 127.2,
127.8, 128.0, 128.7, 135.5, 138.1, 142.1, 150.1, 160.7,
were washed with brine, dried over anhydrous Na2SO4,
filtered, and concentrated in vacuo to yield 0.77 g (99 %)
1
20 as an orange oil. Rf = 0.5 (ethyl acetate); H NMR
(300 MHz, CDCl3): d = 3.03 (t, 2H, J = 6.3 Hz), 3.69 (t,
2H, J = 6.3 Hz), 4.05 (s, 2H), 4.49 (s, 2H), 7.32 (m, 6H),
7.51 (d, 1H, J = 7.7 Hz), 7.86 (d, 1H, J = 8.0 Hz) ppm;
13C NMR (75 MHz, CDCl3): d = 30.0, 34.0, 70.1, 73.4,
123.6, 127.7, 127.9, 128.2, 128.7, 128.8, 135.3, 138.0,
-
189.8 ppm; MS: m/z calcd. for C20H20NO6 [M-H?]-
370.13, found 370.1.
2-[2-[2-(Benzyloxy)ethyl]-6-nitrophenyl]acetic acid
(20, C17H17NO5)
-
141.6, 150.6, 175.5 ppm; MS: m/z calcd. for C17H16NO5
[M-H?]- 314.10, found 314.1.
To an ice-cooled solution of 0.91 g 19 (2.46 mmol) in
5 cm3 THF was added 2 % NaOH (6.38 mmol). After
stirring for 10 min at 0 °C, 30 % H2O2 (4.92 mmol) was
added and the solution was brought to room temperature
and stirred for 1 h. The pH was then adjusted to 1.5 by
careful addition of 2 N HCl and the reaction mixture was
extracted with ethyl acetate. The pooled organic layers
4-(2-Hydroxyethyl)indolin-2-one (2)
A mixture of 0.51 g 20 (1.63 mmol) and 60 mg 10 % Pd-C
catalyst in 10 cm3 EtOH was hydrogenated under balloon
pressure at room temperature for 5 h. The catalyst was then
removed by filtration on CeliteÒ and the solvent evaporated
123

C. Matera et al.
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in vacuo to afford 0.26 g (90 %) 2 as a white solid.
Rf = 0.3 (ethyl acetate); m.p.: 146–148 °C, crystallized
from CH3CN ([7] 147–149 °C); 1H NMR (300 MHz,
CD3OD): d = 2.76 (t, 2H, J = 6.6 Hz), 3.48 (s, 2H), 3.76
(t, 2H, J = 6.6 Hz), 6.72 (d, 1H, J = 7.7 Hz), 6.86 (d, 1H,
J = 7.7 Hz), 7.13 (dd, 1H, J = 7.7 Hz) ppm; 13C NMR
(75 MHz, CD3OD): d = 35.0, 36.2, 61.8, 107.6, 122.8,
125.1, 127.8, 135.6, 143.1, 178.7 ppm; MS: m/z calcd. for
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C10H12NO2 [M?H?]? 178.09, found 178.1.
?
Acknowledgments This research project was financially supported
by the Italian Ministry of Education, University and Research, PRIN
grant 2009R7WCZS to MDA. CM wishes to thank the University of
Milan for a postdoctoral fellowship.
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